U.S. patent number 6,410,603 [Application Number 09/871,744] was granted by the patent office on 2002-06-25 for active topical skin protectants using combinations of reactive nanoparticles and polyoxometalates or metal salts.
This patent grant is currently assigned to Emory University, Nanoscale Materials, Inc., The United States of America as represented by the Secretary of the Army. Invention is credited to Eric Boring, Ernest H. Braue, Shawn Decker, Craig L. Hill, Stephen T. Hobson, Kenneth J. Klabunde, Olga Koper, Erich K. Lehnert, Jeffrey Rhule.
United States Patent |
6,410,603 |
Hobson , et al. |
June 25, 2002 |
Active topical skin protectants using combinations of reactive
nanoparticles and polyoxometalates or metal salts
Abstract
A topical skin protectant formulation containing a barrier cream
and a active moiety for protecting warfighters and civilians
against all types of harmful chemicals, specifically chemical
warfare agents (CWAs). The topical skin protectant offers a barrier
property and an active moiety that serves to neutralize chemical
warfare agents into less toxic agents.
Inventors: |
Hobson; Stephen T. (Belcamp,
MD), Braue; Ernest H. (Witeford, MD), Lehnert; Erich
K. (Rosemont, MD), Klabunde; Kenneth J. (Manhattan,
KS), Decker; Shawn (Manhattan, KS), Hill; Craig L.
(Atlanta, GA), Rhule; Jeffrey (Franklin, OH), Boring;
Eric (Diamondhead, MS), Koper; Olga (Manhattan, KS) |
Assignee: |
The United States of America as
represented by the Secretary of the Army (Washington, DC)
Nanoscale Materials, Inc. (Atlanta, GA)
Emory University (Atlanta, GA)
|
Family
ID: |
26904065 |
Appl.
No.: |
09/871,744 |
Filed: |
June 1, 2001 |
Current U.S.
Class: |
514/759; 424/59;
514/723; 514/772; 514/789; 514/844; 514/845; 514/937; 514/944 |
Current CPC
Class: |
A61K
8/11 (20130101); A61K 8/19 (20130101); A61K
8/24 (20130101); A61K 8/29 (20130101); A61K
8/70 (20130101); A61K 8/8123 (20130101); A61K
31/02 (20130101); A61K 31/08 (20130101); A61Q
17/00 (20130101); A62D 3/30 (20130101); B82Y
5/00 (20130101); A61K 8/0241 (20130101); A61K
2800/413 (20130101); A62D 2101/02 (20130101); Y10S
514/944 (20130101); Y10S 514/844 (20130101); Y10S
514/937 (20130101); Y10S 514/845 (20130101) |
Current International
Class: |
A61K
8/70 (20060101); A61K 8/72 (20060101); A61K
8/30 (20060101); A61K 31/08 (20060101); A61K
8/81 (20060101); A61K 31/02 (20060101); A61K
31/075 (20060101); A61K 8/04 (20060101); A61K
8/19 (20060101); A61K 8/29 (20060101); A62D
3/00 (20060101); A61K 8/24 (20060101); A61K
8/11 (20060101); A61Q 17/00 (20060101); A61K
031/02 (); A61K 031/08 (); A61K 047/00 (); A61K
007/42 () |
Field of
Search: |
;424/59
;514/723,759,772,789,844,845,937,939,944 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Smith, et al., Jrnl. of the American Acad. of Dermatology, Vo. 32,
No. 5, part 1, May 1995, pp. 765-776, Sulfur mustard: Its
continuing threat as a chemical warfare agent, the cutaneous
lesions induced, progress in understanding its mechanism of action,
its long-term health effectgs, and new developments for protection
and therapy. .
Arroyo, er al., Jrnl. of Pharm. and Toxicol. Methods, vol. 33, No.
2, Apr. 1995, pp. 109-112, EPR/Spin-Label Technique as an
Analytical Tool for Determining the Resistance of Reactive Topical
Skin Protectants (rTSPs) to the Breakthrough of Vesicant
Agents..
|
Primary Examiner: Dodson; Shelley A.
Attorney, Agent or Firm: Arwine; Elizabeth
Parent Case Text
PRIORITY INFORMATION
This application claims the benefit of priority of U.S. Provisional
Application No. 60/209,337 filed Jun. 2, 2000.
Claims
What is claimed is:
1. A topical skin protectant formulation for neutralizing chemical
warfare agents into less toxic products comprising: a barrier base
cream; and one or more polyoxometalate suspended on reactive
nanoparticles or metal salt suspended on reactive nanoparticles as
an active moiety.
2. The topical skin protectant formulation of claim 1, wherein the
base cream comprises poly(tetrafluoroethylene) resins dispersed in
perfluorinated polyether oils.
3. The topical skin protectant formulation of claim 1, wherein said
polyoxometalate or metal salt comprises Na.sub.5 PV.sub.2 Mo.sub.10
O.sub.40, Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40, H.sub.5 PV.sub.2
Mo.sub.10 O.sub.40, Ce(NO.sub.3).sub.3, or Cu(NO.sub.3).sub.2, and
said reactive nanoparticle is conventionally prepared
nanoparticulate MgO, ZnO, CaO, TiO.sub.2 or CeO.sub.2 ; or Aerogel
prepared nanoparticulate MgO, ZnO, CaO, TiO.sub.2, or
CeO.sub.2.
4. A topical skin protectant formulation for neutralizing chemical
warfare agents into less toxic products comprising:
(a) a barrier base cream, said barrier base cream comprising
poly(tetrafluoroethylene) resins dispersed in perfluorinated
polyether oils; and
(b) one or more active moieties complex comprising a
polyoxometalate or metal salt suspended on reactive nanoparticles,
wherein said polyoxometalate or metal salt comprises: Na.sub.5
PV.sub.2 Mo.sub.10 O.sub.40, Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40,
H.sub.5 PV.sub.2 Mo.sub.10 O.sub.40, Ce(NO.sub.3).sub.3, or
Cu(NO.sub.3).sub.2, and said reactive nanoparticle is one or more
conventionally prepared nanoparticulate MgO, ZnO, CaO, TiO.sub.2 or
CeO.sub.2 ; or Aerogel prepared nanoparticulate MgO, ZnO, CaO,
TiO.sub.2, or CeO.sub.2.
5. The topical skin protectant formulation of claim 4, further
comprising one or more additives.
6. The topical skin protectant formulation of claim 5, wherein said
additives comprise one or more of water, stabilizers, surfactants,
camouflage paints, and sunscreens.
7. A topical skin protectant formulation for neutralizing chemical
warfare agents into less toxic products comprising:
(a) a barrier base cream, said barrier base cream comprising
poly(tetrafluoroethylene) resins dispersed in perfluorinated
polyether oils;
(b) one or more active moiety complex comprising a polyoxometalate
or metal salt suspended on reactive nanoparticles, wherein said
polyoxometalate or metal salt comprises: Na.sub.5 PV.sub.2
Mo.sub.10 O.sub.40, Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40, H.sub.5
PV.sub.2 Mo.sub.10 O.sub.40, Ce(NO.sub.3).sub.3, or
Cu(NO.sub.3).sub.2 and said reactive nanoparticle is one or more
conventionally prepared nanoparticulate MgO, ZnO, CaO, TiO.sub.2 or
CeO.sub.2 ; or Aerogel prepared nanoparticulate MgO, ZnO, CaO,
TiO.sub.2, or CeO.sub.2 ; and
(c) one or more additives.
8. The topical skin protectant formulation of claim 7, wherein said
additives comprise one or more of water, surfactants, stabilizers,
camouflage paints, and sunscreens.
9. A topical skin protectant system comprising:
(a) a topical skin protectant formulation for neutralizing chemical
warfare agents into less toxic products comprising a barrier cream
and one or more active moieties, said active moieties comprising
polyoxometalates and/or metal salts and/or reactive nanoparticles;
and
(b) a second formulation for applying a thin solid active moiety
powder on top or below said topical skin protectant formulation
comprising one or more polyoxometalates and/or metal salts and/or
reactive nanoparticles.
10. The topical skin protectant system of claim 9, wherein said one
or more active moieties in the topical skin protectant formulation
and in the solid active moiety powders are one or more active
moieties comprising a complex comprising one or more conventionally
prepared nanoparticulate MgO, ZnO, CaO, TiO.sub.2 or CeO.sub.2 ; or
Aerogel prepared nanoparticulate MgO, ZnO, CaO, TiO.sub.2, or
CeO.sub.2 and a polyoxometalate or metal salt comprising Na.sub.5
PV.sub.2 Mo.sub.10 O.sub.40, Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40,
H.sub.5 PV.sub.2 Mo.sub.10 O.sub.40, Ce(NO.sub.3).sub.3, or
Cu(NO.sub.3).sub.2.
11. A method of protecting a user against chemical warfare agents
comprising: applying a topical skin protectant formulation for
neutralizing chemical warfare agents into less toxic products
comprising:
(a) a barrier cream; and
(b) one or more active moieties, said one or more active moieties
comprising polyoxometalates and/or metal salts and/or reactive
nanoparticles.
12. A method of protecting a user against chemical warfare agents
comprising:
(a) applying a first thin layer of solid active moiety powder
comprising one or more polyoxometalates and/or metal salts and/or
reactive nanoparticles; and
(b) applying a second layer of a topical skin protectant
formulation for neutralizing chemical warfare agents into less
toxic products comprising a barrier cream and one or more active
moieties comprising one or more complex of one or more
polyoxometalates and/or one or more metal salts and/or reactive
nanoparticles.
13. The method of claim 12, wherein said one or more active
moieties in the topical skin protectant formulation and in the
solid active moiety powder are polyoxometalates and/or metal salts
and/or reactive nanoparticles selected from the group consisting
of:
(a) [Na.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]TiO.sub.2,
(b) [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]Aerogel-MgO,
(c) [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]ZnO,
(d) [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]Aerogel-TiO.sub.2,
and
(e) [2 mol % (Ce(NO.sub.3).sub.3
+Cu(NO.sub.3).sub.2)]Aerogel-TiO.sub.2.
14. A method of protecting a user against chemical warfare agents
comprising:
(a) applying a first layer of a topical skin protectant formulation
for neutralizing chemical warfare agents into less toxic products
comprising a barrier cream and one or more active moieties, said
one or more active moieties comprising one or more polyoxometalates
and/or metal salts and/or reactive nanoparticles; and
(b) applying a thin layer of solid active moiety powder over the
first layer, said solid active moiety powder comprising one or more
polyoxometalates and/or metal salts and/or reactive
nanoparticles.
15. The method of claim 14, wherein said one or more active
moieties in the topical skin protectant formulation and in the
solid active moiety powder are polyoxometalates and/or metal salts
and/or reactive nanoparticles selected from the group consisting
of:
(a) [Na.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]TiO.sub.2,
(b) [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]Aerogel-MgO,
(c) [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]ZnO,
(d) [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]Aerogel-TiO.sub.2,
and
(e) [2 mol % (Ce(NO.sub.3).sub.3
+Cu(NO.sub.3).sub.2)]Aerogel-TiO.sub.2.
16. A method of making a topical skin protectant formulation
comprising: mixing:
a) one or more active moieties comprising polyoxometalates and/or
metal salts and/or reactive nanoparticles: with
b) a barrier cream comprising poly(tetrafluoroethylene) resins
dispersed in perfluorinated polyether oils.
17. The method of claim 16, wherein said polyoxometalates and/or
metal salts and/or reactive nanoparticles are selected from the
group consisting:
(a) [Na.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]TiO.sub.2 (N),
(b) [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]Aerogel-MgO,
(c) [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]ZnO,
(d) [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]Aerogel-TiO.sub.2,
and
(e) [2 mol % (Ce(NO.sub.3).sub.3
+Cu(NO.sub.3).sub.2)]Aerogel-TiO.sub.2.
18. A topical skin protectant formulation comprising a formulation
selected from the group consisting of:
(a) about 5 wt. % of polyoxometalate Na.sub.5 PV.sub.2 Mo.sub.10
O.sub.40 on titanium dioxide, about 48 wt. % perfluoropolyether
oil, about 48 wt. % perfluoropolyethylene;
(b) about 4 wt. % of polyoxometalate Ag.sub.5 PV.sub.2 Mo.sub.10
O.sub.40 on aerogel prepared magnesium oxide about 50 wt. %
perfluoropolyether oil, about 48 wt. % perfluoropolyethylene;
(c) about 3 wt. % polyoxometalate Ag.sub.5 PV.sub.2 Mo.sub.10
O.sub.40 on zinc oxide, about 50 wt. % perfluoropolyether oil,
about 48 wt. % perfluoropolyethylene;
(d) about 3 wt. % polyoxometalate Ag.sub.5 PV.sub.2 Mo.sub.10
O.sub.40 on aerogel prepared titanium dioxide, about 50 wt. %
perfluoropolyether oil, about 48 wt. % perfluoropolyethylene;
and
(e) about 2.5 wt. % metal salt Ce(NO.sub.3).sub.3 and
Cu(NO.sub.3).sub.2 on titanium dioxide, about 50 wt. %
perfluoropolyether oil, about 47.5 wt. % perfluoropolyethylene.
19. A topical skin protectant formulation for neutralizing chemical
warfare agents into less toxic products comprising:
(a) a barrier base cream, said barrier base cream comprising about
30-50 wt. % poly(tetrafluoroethylene) resins dispersed in about
40-60 wt. % perfluorinated polyether oils; and
(b) about 1-20 wt. % active moiety, said active moiety comprising a
complex of a polyoxometalate and/or metal salt suspended on
reactive nanoparticles; said reactive nanoparticles selected from
the group consisting of one or more conventionally prepared
nanoparticulate MgO, ZnO, CaO, TiO.sub.2 or CeO.sub.2 ; or Aerogel
prepared nanoparticulate MgO, ZnO, CaO, TiO.sub.2, or CeO.sub.2 and
said one or more polyoxometalates or metal salts selected from the
group consisting of Na.sub.5 PV.sub.2 Mo.sub.10 O.sub.40, Ag.sub.5
PV.sub.2 Mo.sub.10 O.sub.40, and H.sub.5 PV.sub.2 Mo.sub.10
O.sub.40, Ce(NO.sub.3).sub.3, or Cu(NO.sub.3).sub.2.
20. A topical skin protectant formulation for neutralizing chemical
warfare agents into less toxic products comprising: an active
moiety, wherein said active moiety is a polyoxometalate of the
formula Y.sub.n [XM.sub.x M'.sub.12-x O.sub.40 ], where M=redox
active d-block or f-block metal, including d.sup.0 centers such as
V(V), x=1-6, M'=Mo(VI) and/or W(VI), Y=the counter cations, which
can be s-block metals (e.g. Na(I), Ca(II), etc.), d-block metals
(e.g. Ag(I), Cu(II), Au(III), etc.), f-block metals (e.g. Ce(IV),
etc.), or p-block based cations such as tetra-n-butylammonium, or
any combination of these four classes of counter cations, and n=the
number of counter cations, A, such that their combined positive
charge equals the negative charge on the POM unit, [XM.sub.x
M'.sub.12-x O.sub.40 ].sup.n-.
21. The topical skin protectant of claim 20, further comprising a
base cream.
22. A topical skin protectant formulation for neutralizing chemical
warfare agents into less toxic products comprising one or more
active moieties, wherein said one or more active moiety is a
complex comprising a polyoxometalate or metal salt suspended on
reactive nanoparticles.
23. The topical skin protectant formulation of claim 1, wherein
said chemical warfare agents are one or more of the group
consisting of blistering agents, G class nerve agents, and VX.
24. The topical skin protectant formulation of claim 23, wherein
said blistering agent is sulfur mustard.
25. The topical skin protectant formulation of claim 23, wherein
said G class nerve agent is soman.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to active topical skin protectants. More
specifically, the invention relates to an active barrier cream for
protection against all types of harmful chemicals, specifically
chemical warfare agents (CWAs). The active barrier cream is applied
prior to exposure on the skin of persons at risk of exposure to
harmful chemicals to provide a protective barrier for the skin. The
active barrier cream chemically or physically reacts with harmful
chemicals such as CWAs (vesicants and nerve agents) to neutralize
these harmful chemicals while the barrier properties of the cream
prevent penetration of harmful chemicals through the cream to the
skin.
2. Description of Related Art
The concept of applying a topical protectant to vulnerable skin
surfaces before entry into a chemical combat arena has been
proposed as a protective measure against percutaneous CWA toxicity
since the first use of CWAs in World War I. The protectant was
applied to vulnerable skin surfaces prior to entry into a chemical
combat area. Topical protectants should augment the protection
afforded by the protective overgarments and/or redefine the
circumstances requiring mission oriented protective posture (MOPP)
levels. The rapid action of vesicating agents, also known as
blistering agents, such as sulfur mustard (HD) and lewisite (L),
require a pre-exposure skin protection system or a contamination
avoidance approach that may preclude the percutaneous toxicity of
these agents. These approaches also reduce the risk of exposure to
organophosphorus (OP) chemical agents (nerve agents), which unlike
the vesicating agents, are lethal in droplet amounts.
An organic molecule, S-330, that reacts with CWAs was incorporated
in a product and fielded as the M-5 ointment kit at the end of
World War II (Formula 1). ##STR1##
However, the unacceptable barrier properties and the undesirable
cosmetic properties (specifically foul odor and sticky texture)
caused a recall of this product.
Two non-active topical skin protectant (TSP) formulations were
developed at the United States Army Medical Research Institute of
Chemical Defense (USAMRICD) and were transferred to advanced
development following a Milestone Zero (MS0) Review in October
1990. The timeline of the approval of the TSP continued with MSI in
1993, a Investigational New Drug (IND) filed with the FDA in 1994,
MSII in 1995, and culminated with New Drug Application (NDA)
approval in February, 2000. Upon approval by the FDA, the TSP was
designated Skin Exposure Reduction Paste Against Chemical Warfare
Agents (SERPACWA). SERPACWA is a 50:50 (wt/wt) mixture of
perfluoropolyether oil (Fomblin.RTM. Y25 from Ausimont) and
poly(tetrafluoroethylene) (polymist.RTM. F5a powder from Ausimont).
The formulation described in McCreery U.S. Pat. No. 5,607,979 is
directed to a topical skin protectant cream that acts as a barrier
to CWAs.
Although SERPACWA extends the protection afforded by MOPP and
allows a longer window for decontamination, it does not completely
remove the possibility for contamination because the CWA is not
neutralized. To avoid contamination of other areas of the
battlefield and to preclude the future percutaneous absorption of
the CWA, decontamination is still required. Furthermore, although
the McCreery formulation provides excellent protection against GD
and HD liquid, its protection against HD vapor is minimal.
To overcome these deficiencies, there is a need for a new TSP that
contains an active component. This active Topical Skin Protectant
(active TSP) was developed within the following criteria. First,
the active TSP should neutralize CWAs including but not limited to
sulfur mustard (HD), soman (GD), and VX. Second, the barrier
properties of the TSP should be maintained or increased. Third, the
protection against HD vapor should increase. And fourth, the
cosmetic characteristics (i. e. odor, texture) of the TSP should be
maintained.
This invention meets the above criteria and solves the problems
associated with the past TSPs by providing an active topical skin
protectant that increases effectiveness of the TSP barrier quality
and neutralizes CWAs into less harmful products.
It is therefore, an objective of the present invention to provide
an active topical skin protectant that prevents the percutaneous
absorption of CWAs and converts these toxic materials into less
harmful products.
It is a further objective of the present invention to provide an
active topical skin protectant that maintains desirable cosmetic
properties making it acceptable to the user. Specifically, the
active TSP should not be sticky, should be without offensive odor,
and should be nonirritating to the skin.
It is still a further object of the invention to provide an active
topical skin protectant that is practical for field operations.
Specifically, the active TSP should have a stable shelf life, not
be easily washed off with water, and should not react with
insecticides or camouflage paint.
SUMMARY OF THE INVENTION
A topical skin protectant formulation for neutralizing chemical
warfare agents into less toxic products comprising: a barrier base
cream and one or more active moieties. The base cream comprises
poly(tetrafluoroethylene) resins dispersed in perfluorinated
polyether oils. The active moieties that have been found to be
effective with the base cream are listed in Table 1. The active
barrier cream is applied to the skin prior to exposure of persons
at risk of exposure to harmful chemicals to provide an active
barrier to protect the skin. The active barrier cream chemically or
physically reacts with harmful chemicals such as CWAs to neutralize
these harmful chemicals while the barrier properties of the cream
prevent penetration of harmful chemicals through the cream to the
skin.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a flow diagram of the active TSP Decision Tree Network
for efficacy evaluation.
DETAILED DESCRIPTION
Candidate Active Moieties
The types of materials that neutralize harmful agents use three
main modes of action: oxidation, reduction or hydrolysis.
Operating criteria, however, restricts the selection of the active
materials. Thus, the active moiety must not irritate the skin,
react with insecticides or camouflage paints or be unstable. This
restriction eliminates many of the most active species.
Furthermore, the active moiety must be incorporated into a highly
fluorinated environment that is not amenable to many reaction
pathways. One class of compound that is amenable to these
conditions is composite materials composed of reactive
nanoparticles (RNPs) and polyoxometalates (POMs) or metal
salts.
TABLE 1 LIST OF EXAMPLE ACTIVE COMPOUNDS AND EXAMPLE FORUMLATIONS
FOR ACTIVE TOPICAL SKIN PROTECTANTS USING COMBINATIONS OF REACTIVE
NANOPARTICLES AND POLYOXOMETALATES OR METAL SALTS Example
Formulation % % % ICD # Active POM/Nanoparticle Active PFPE PTFE
3353 [Na.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]Aerogel-TiO.sub.2 5
47.5 47.5 3520 [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]Aerogel-MgO
2.5 49.7 47.8 3522 [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]ZnO 2.5
50.1 47.5 3524 [Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40
]Aerogel-TiO.sub.2 2.6 49.8 47.6 3633 [2 mol % (Ce(NO.sub.3).sub.3
+ 2.5 50 47.5 Cu(NO.sub.3).sub.2)]Aerogel-TiO.sub.2 Abbreviations:
PTFE: poly(tetrafluoroethylene) available as F5A powder from
Ausimont, Morristown, NJ PFPE: perfluoropolyether available as
FOMBLIM .TM. Y25 oil from Ausimont, Morristown, NJ Percentages are
weight percents
For purposes of description, there are 3 hierarchies, gradations,
designations or classes of POMs. The first, most encompassing class
of the 3 below covers all POMs of the Keggin class. The second
gradation or class is those POMs that contain vanadium (V) centers
as the redox active component, and the third class are the POMs
listed in Table 1 above.
POMs--First Class:
Y.sub.n [XM.sub.x M'.sub.12-x O.sub.40 ], where M=redox active
d-block or f-block metal, including d.sup.0 centers such as V(V),
x=1-6, M'=Mo(VI) and/or W(VI), Y=the counter cations, which can be
s-block metals (e.g. Na(I), Ca(II), etc.), d-block metals (e.g.
Ag(I), Cu(II), Au(III), etc.), f-block metals (e.g. Ce(IV), etc.),
or p-block based cations such as tetra-n-butylammonium, or any
combination of these 4 classes of counter cations, and n=the number
of counter cations, A, such that their combined positive charge
equals the negative charge on the POM unit, [XM.sub.x M'.sub.12-x
O.sub.40 ].sup.n-.
POM Second Class:
The POMs above, but where M=V(V).
POM Third Class:
H.sub.5 PV.sub.2 Mo.sub.10 O.sub.40, Ag.sub.5 PV.sub.2 Mo.sub.10
O.sub.40, or Na.sub.5 PV.sub.2 Mo.sub.10 O.sub.40.
The percent values assigned to the above listed components of the
example skin protectant formulations are given for example only.
These values may be adjusted up or down and still embody the spirit
of the invention if the herein described qualities of efficacy and
composition of the present invention are met. The active moiety may
be present in the range of about 1-20%, the PFPE may be present in
the range of about 40-60% and the PTFE may be present in the range
of about 30-50%.
All active moieties listed above are useful for both liquid and
vapor challenges. The active moieties are polyoxometalates or metal
salts suspended on reactive nanoparticles. These POMs were
suspended either on conventionally prepared nanoparticulate zinc
oxide (ICD 3520) or on aerogel prepared nanoparticulate titanium
dioxide or magnesium oxide (ICD 3522, 3524). The metal salts were
suspended on aerogel prepared nanoparticulate titanium dioxide (ICD
3633). The process for the preparation of aerogel metal oxides is
covered in a patent filed by Klabunde et al (U.S. Pat. No.
6,087,294) and Utarpanya et al., Chem Mater. 3:175-181 (1991),
incorporated herein by reference. The amount of each varies with
each formulation. The object is to optimize the quantity of active
moiety in the base cream without loosing the barrier properties of
the base cream. One criterion for selection of the active materials
is increased efficacy against HD and/or GD vapor. Formulations that
have significantly (P=0.05) increased protection compared to
SERPACWA (ICD 3004) in the penetration cell model against HD and GD
are listed in the results section. The best candidate compound
listed in Table 1 for both HD and GD is ICD 3524 ([Ag.sub.5
PV.sub.2 Mo.sub.10 O.sub.40 ]TiO.sub.2).
The POM/RNP must also be incorporated into the TSP matrix without
degradation of the barrier properties. These materials were
incorporated into the cream either as solids or aqueous
suspensions. Typically they are dispersed into the perfluorinated
oil followed by sequential addition of the appropriate amount of
F5A poly(tetrafluoroethylene).
SERPACWA (ICD 3004) consists of fine particles of
poly(tetrafluoroethylene) resin dispersed in perfluorinated
polyether oil. The excellent barrier properties of this high
molecular weight polymer formulation are related to the low
solubility of most materials in it. Only highly fluorinated
solvents like Freon.RTM. have been observed to show appreciable
solubility. This aprotic non-polar polymer mixture provides a
unique medium for active moieties of the invention. Reaction
mechanisms that do not involve charged transition states should be
favored in this chemical environment.
Base creams formed from about 35-50% fine particulates of certain
poly(tetrafluoroethylene) PTFE resins dispersed in perfluorinated
polyether oils (PFPE) having viscosities from about 20 cSt to about
500 cSt afford good protection against chemical warfare agents such
as HD, L, sulfur mustard/Lewisite mixtures (HL), pinacolyl
methylphosphonofluoridate (soman or GD)), thickened soman (TGD) and
O-ethyl S-(2-diisopropylaminoethyl)methylphosphonothiolate (VX).
PTFE and PFPE are available commercially from Ausimont (Morristown,
N.J.) and Dupont (Wilmington, Del.).
The base creams used in the invention are suspensions of 35-50%
finely divided PTFE having a surface area below about 6 m.sup.2 /g
in a perfluorinated polyether base oil prepared from
perfluoropropylene oxide, which has a viscosity between about 20
and about 500 cSt. More preferred compositions comprise from about
35% to about 50% of finely divided PTFE having an average particle
size from about 0.1 .mu.m to about 10 .mu.m and a surface area
below about 4 m.sup.2 /g in a perfluorinated polyether base oil
from 40% to 60% having a viscosity between about 20 and about 500
cSt.
Suitable perfluorinated polyether oils are Fomblin.RTM. HC- and
Y-oils (Ausimont) and Krytox.RTM. oils (Dupont). The Fomblin.RTM.
oils are mixtures of linear polymers based on perfluoropropylene
oxide having the following chain structure: CF.sub.3
--[(OCF(CF.sub.3)CF.sub.2).sub.n --(OCF.sub.2).sub.m ]OCF.sub.3.
The Krytox.RTM. oils are mixtures of linear polymers also based on
perfluoropropylene oxide and have the chemical structure
F--[(CF(CF.sub.3)CF.sub.2 O)].sub.m CF.sub.2 CF.sub.3. Fomblin.RTM.
Z oils having the formula: CF.sub.3 --[(OCF.sub.2 CF.sub.2).sub.n
--(OCF.sub.2).sub.m ]--OCF.sub.3, may also be useful in the
practice of the invention. The indices n and m indicate the average
number of repeating polymeric subunits in the oil molecules. The
oils may have a viscosity of about 20 cSt to about 500 cSt or more.
The creams were generally prepared according to U.S. Pat. No.
5,607,979, incorporated herein in its entirety.
Other additives to the base cream are water and surfactant and
other chemical necessary to maintain activity (see Table 1). The
surfactant facilitates the mixing of the water with the base cream.
An example of a typical surfactant is perfluoropolyalkylether
(Krytox.RTM. CAS # 60164-51-4 from Dupont). Additional materials
may also be incorporated as long as they do not reduce
effectiveness of the topical protectant, such as stabilizers,
camouflage paints, and sunscreens.
A further understanding of the composition of the topical
protectant of the invention can be obtained by reference to certain
specific example formulations set forth in Table 1. These examples
are provided herein for purposes of illustration only and are not
intended to be limiting. Many active moieties require the presence
of water as a reagent for the hydrolysis of HD and GD. The active
moieties that react by a hydrolysis mechanism require the presence
of water. When the topical protectant is applied to the skin of a
user, moisture in the form of perspiration may also aid in the
hydrolysis of HD and GD. The addition of perfluorinated polyether
surfactants to the base cream facilitates the addition of
water.
Description of Mixing the POMs and RNPs
Supporting polyoxometalates or metal salts on the reactive
nanoparticles is a relatively straightforward procedure. Depending
on the oxygen sensitivity of the material, some of the
polyoxometalate/metal salt/reactive nanoparticle materials may be
held under inert atmosphere during the procedure. The procedure may
be generally described by dissolving the desired amount of
polyoxometalate or metal salt in an appropriate solvent and then
adding the desired amount of reactive nanoparticle material to the
solution. Mechanical mixing times of 10-20 minutes are usually
sufficient for the adsorption of the polyoxometalate or metal salt
onto the surface of the reactive nanoparticle. A typical procedure
for the preparation of polyoxometalate or metal salt supported on
reactive nanoparticles is presented below.
In a 50 ml septum capped round bottom flask is placed 30 ml of
toluene or other suitable solvent. Added to this is 0.4582 g of
Na.sub.5 PV.sub.2 Mo.sub.10 O.sub.40. The solution is stirred to
dissolve the polyoxometalate and then 0.5000 g of Aerogel prepared
nanoparticulate MgO is added. The polyoxometalate/reactive
nanoparticle mixture is allowed to stir overnight. After stirring,
the solvent and polyoxometalate/reactive nanoparticle formulation
are separated either through filtration or vacuum evaporation of
the solvent. This yields approximately 0.95 grams of 2 mol %
Na.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 polyoxometalate supported on
Aerogel prepared nanoparticulate MgO.
Temperature and mixing sheer should be monitored to maintain the
base cream at the desired consistency and quality. The active TSPs
are typically prepared at ambient temperature using mechanical
mixing. Depending on the oxygen sensitivity of the active material,
some of the polyoxometalate/metal salt/reactive nanoparticle
formulation may be added to the perfluorinated oil under an inert
(i. e. nitrogen) atmosphere. Mixing times of 10-20 minutes are
usually sufficient for dispersal of the polyoxometalate/metal
salt/reactive nanoparticle formulation into the SERPACWA matrix. A
typical procedure for the preparation of an active aTSP with a
POM/metal salt/reactive nanoparticle formulation is presented
below:
In a polypropylene container is added the appropriate amount of
POM/RNP (1-3% by weight) and Y25 (50-55% by weight) perfluorinated
oil. The suspension is mixed with a mechanical stirrer at ambient
temperature for 5 to 15 minutes. To the suspension is added F5A
poly(tetrafluoroethylene) in three portions with vigorous
mechanical stirring for 5 to 10 minutes between each addition.
After final addition the container is tightly capped and sealed
with Parafilm.RTM..
Multilayer Approach
Although an active TSP can be generally the application of a powder
that is a POM/RNP sprinkled on the skin, or an active moiety in a
base cream wherein the cream is spread on the skin, a multilayering
approach can also be used. The multilayer approach would be to use
the active TSP as the first layer and a solid active moiety powder
as the second layer. The second layer would be a thin coating of
the solid active moiety powder sprinkled over the active TSP cream.
This approach would provide a concentrated decontamination material
at the surface of the barrier cream, which would accelerate the
neutralization process of CWA's coming in contact with the surface.
In the alternative, the solid active moiety powder can be applied
first followed by an application of the active TSP.
Testing
Evaluation of formulations was conducted with a decision tree
network (DTN) that describes the path that active TSPs follow
during evaluation (FIG. 1).
The DTN is divided into two pathways: one for vesicants and the
other for nerve agents. Within these pathways there are three
blocks each with a decision point. The first block consists of a
series of three mechanical (in vitro) modules used to determine the
initial efficacy of candidate formulations and to eliminate
non-effective candidates before animal testing, the second block
consists of in vivo modules and the third block consists of an
advanced animal module to determine the influence of time, water
and interactions with other products.
The M8 paper test is used to evaluate the barrier resistance of
liquid CWA challenges, including HD, pinacolyl
methylphosphonofluoridate (soman, GD), and O-ethyl
S-(2-diisopropylaminoethyl) methylphosphonothioate (VX). In this
test a 0.15 mm layer of active TSP is placed over a well-defined
area of M8 chemical detection paper and challenged with an 8 .mu.l
droplet of CWA. When agent penetrates the active TSP barrier and
reaches the M8 paper, a colored spot develops on the paper. The
test assemblies are observed for 6 hr and the breakthrough time is
reported for each sample. A total of nine replicates are run for
each test, and a standard reference compound is included each day
for quality control.
The penetration cell test is used to evaluate the barrier
properties against both liquid and vapor CWA challenges (Braue, E.
H. Jr. Journal of Applied Toxicology, 1999, 19(S), S47-S53). In
this test the lower half of a Reifenrath diffusion cell (Reifenrath
Consulting and Research, Richmond, Calif.) is used. A 0.15 mm thick
layer of active TSP is supported by nitrocellulose paper on top of
the cell. The active TSP layer is challenged with a 10-ul liquid
droplet of HD or an 8 .mu.l droplet of GD, or a saturated vapor cup
of HD or GD. Breakthrough of CWA into the lower chamber of the
diffusion cell is monitored using a miniature continuous air
monitoring system (MINICAMS, CMS Research, Birmingham, Ala.). This
system has been automated to allow continuous monitoring of five
cells in a 40-min cycle. The test runs for 20 hr and the
accumulated amounts of agent that break through the active TSP
barrier are calculated. From these data, we obtained two values:
the cumulative amount of CWA that penetrates through the active
TSP, and the time at which a "breakthrough" occurs. We defined
"breakthrough" values at the minimum amount of HD (1000 ng) and GD
(1000 ng) that results in a physiological response. Minimal amount
of HD for vesication=1000 ng. See F. R. Sidell, J. S. Urbanetti, W.
J. Smith, and C. G. Hurst in Textbook of Military Medicine, Medical
Aspects of Chemical and Biological Warfare, edited by F. R. Sidell,
E. T. Takafuji, and D. R. Franz (Office of the Surgeon General at
TMM Publications, Washington, D.C. 1997) p 201. LD.sub.50 for soman
(GD)=350 mg(70 kg man. See F. R. Sidell in Textbook of Military
Medicine, Medical Aspects of Chemical and Biological Warfare,
edited by F. R. Sidell, E. T. Takafuji, and D. R. Franz (Office of
the Surgeon General at TMM Publications, Washington, D.C. 1997) p
141. These two values allow us to rank the active TSP formulations
and to select the appropriate component for advanced
development.
The proof-of-neutralization test is used to verify that active TSP
formulations actually neutralize CWAs into less toxic materials.
This test uses the headspace solid phase microextraction (HS-SPME)
technique for the collection of CWAs. Samples collected on the
extraction filament are analyzed by gas chromatography/mass
spectroscopy. 100 mg of active TSP formulation are challenged with
0.11 .mu.l of neat CWA (HD, GD, or VX) in a small vial. The
headspace above the mixture is sampled periodically to determine
the amount of CWA remaining in the flask. Efficacy is determined by
the % loss of CWA. Other analytical techniques such as Nuclear
Magnetic Resonance (NMR) and Fourier-Transform Infrared
Spectrometry (FTIR) have also been used in this module.
Formulations that pass this initial set of screens are moved into
the second phase of testing using animal models. The weanling pig
test for HD vapor evaluates a 0.10 to 0.20 mm thick layer of active
TSP spread on the depilated dorsa. The standard saturated vapor cup
is used for a 15-60 min challenge. The effectiveness of the active
TSP is determined by measuring the degree of erythema that
developed on the skin exposure site. Erythema is measured
objectively using a reflectance calorimeter (see Braue, E. H. Jr.
Journal of Applied Toxicology, 1999, 19(S), S47-S53).
The rabbit lesion area ratio (LAR) test is used to evaluate a
challenge by HD liquid. In this test, a 0.10 mm layer of active TSP
spread on the clipped dorsa is challenged with 1.0 .mu.l of liquid
HD. The effectiveness of the active TSP is determined by measuring
the lesion areas of protected and non-protected sites.
The rabbit acetyl cholinesterase (AChE) inhibition test is
performed by applying a 0.10 mm thick layer of active TSP on the
clipped dorsa of rabbit followed by a fixed dose of GD (1
LD.sub.50), TGD (1 LD.sub.50), or VX (20 LD.sub.50). The
effectiveness of the active TSP is determined by lethality and also
by measuring the erythrocyte acetyl cholinesterase activity 0.5, 1,
2, and 24 hr following exposure.
Candidate formulations that pass the in vivo test modules move into
advanced animal testing. These tests are similar to the initial
animal tests with the addition of stresses for wear-time and
washing with water. Interactions with other products that a soldier
might use are also evaluated. These products include camouflage
paints, sunscreens and insecticides.
Results
The polyoxometallate/metal salt/reactive nanoparticle composite
will react to neutralize sulfur mustard via oxidation and/or
dehydrohalogenation (Scheme 1) ##STR2##
These oxidations of dialkylsulfides have been reported for POMs
(Gall, R. D., Hill, C. L.; Walker, J. E. Chem. Mater. 1996, 8,
2523). Also, the reactions of HD with reactive nanoparticles
(Wagner, G. W.; Koper, O. B.; Lukas, E.; Decker, S.; Klabunde, K.
J. J. Phys. Chem. B. 2000, 104, 5118) has been reported.
Against GD vapor, the most effective moiety was the ICD 3524
([Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40 ]TiO.sub.2) that reduced the
amount of GD by 59% compared to TSP alone. In this case, it is
likely that the TiO.sub.2 is acting as the active species (Scheme
2). ##STR3##
The GD may also be physically adsorbed by the POM/RNP or it is
possible that adventitious adsorbed water in the POM/RNP complex
may act as a reagent for hydrolysis presented above.
In the first mechanical test, the M8 paper, POM/RNP formulations
were tested against HD (ICD #3520, 3522, and 3524), GD (ICD #3522,
and 3524), and VX liquid (ICD #3520, 3522, and 3524) (Chart 1).
CHART 1 Breakthrough time and % breakthrough for [POM]RNP
containing active TSPs. ##STR4##
Chart 1. Breakthrough time and % breakthrough for [POM]RNP
containing active TSPs.
All POM/RNP containing active TSPs displayed equivalent or better
barrier against liquid challenges as compared to SERPACWA (ICD
3004). Furthermore, ICD 3520 ([Ag.sub.5 PV.sub.2 Mo.sub.10 O.sub.40
]Aerogel-MgO) displayed no breakthroughs over 360 minutes for both
HD and VX liquid. From the above chart it appears that ICD 3524 has
the best barrier properties against liquid challenges. The increase
in protection for the POM/RNP active TSPs was impressive against GD
vapor as seen by the increase in the time for 1000 ng of GD vapor
to penetrate the active TSP as compared to SERPACWA (ICD 3004)
(Chart 2).
CHART 2 Time for 1000 ng GD to penetrate aTSPs with POM/RNP active
TSPs. ##STR5##
Chart 2. Time for 1000 ng GD to penetrate aTSPs with POM/RNP active
TSPs.
A comparison of the cumulative amount of GD vapor that penetrates
the active TSP over 20 hours also demonstrates the efficacy or
POM/RNP active TSPs (Chart 3).
CHART 3 Cumulative amount of GD vapor through aTSP over 20 hr.
##STR6##
Chart 3. Cumulative amount of GD vapor through aTSP over 20 hr.
Formulation ICD 3524 shows the greatest protection against GD vapor
reducing the amount of GD by 59%. Due to high variability in the
results, only ICD 3524 shows significantly (P=0.05) increased
protection compared to SERPACWA (ICD 3004) in the penetration cell
model against GD.
The increase in protection for the RNP/POM was also remarkable
against HD vapor as demonstrated in the increase in the time needed
for 1000 ng of HD vapor to penetrate the active TSP as compared to
SERPACWA (ICD 3004) (Chart 4).
CHART 4 Time for 1000 ng HD to penetrate active TSPs containing
RNP/POM. ##STR7##
Chart 4. Time for 1000 ng HD to penetrate active TSPs containing
RNP/POM.
A comparison of the cumulative amount of HD vapor that penetrates
the active TSP over 20 hours also shows the increase in protection
(Chart 5).
CHART 5 Cumulative amount of HD vapor through aTSP over 20 hr.
##STR8##
Chart 5. Cumulative amount of HD vapor through aTSP over 20 hr.
As clearly seen in Chart 5, only ICD 3520 ([Ag.sub.5 PV.sub.2
Mo.sub.10 O.sub.40 ]MgO) and ICD 3524 ([Ag.sub.5 PV.sub.2 Mo.sub.10
O.sub.40 ]TiO.sub.2) show significant efficacy (P=0.05) against HD
vapor compared to 3004 (ICD 3004) in the penetration cell model. In
fact, as few as 54 ng of HD vapor penetrate the aTSP barrier in 20
hr.
Despite the excellent performance of the active TSPs containing
polyoxometalate in the penetration cell models, the results from
the weanling pig model were more varied (Chart 6).
CHART 6 Results of active TSPs containing POM/RNP complexes.
##STR9##
Chart 6. Results of active TSPs containing POM/RNP complexes.
The active TSPs containing POM/RNP complexes reduced the cumulative
amount of HD vapor in the penetration cell by up to 90% (Chart 4).
The recorded erythema from HD vapor in these active TSPs, however,
is not significantly decreased above control in the in vivo test.
We offer four possible explanations. First, the skin is occluded by
the aTSP, increasing agent penetration and thus the observed
erythema. Second, the skin may be sensitized by the aTSP, and thus
the small amount of HD vapor that penetrates the skin results in
greater erythema. Third, the skin may be irritated by the reaction
products. And fourth, agent may penetrate the aTSP during exposure
and not be completely removed by the cleaning procedure.
Having now fully described the invention, it will be apparent to
one of ordinary skill in the art that many changes and
modifications can be made thereto without departing from the spirit
or scope of the invention as set forth herein.
* * * * *